Cues associated with natural or drug rewards can acquire such powerful control over behavior that individuals sometimes have difficulty resisting them. Indeed, the ability of reward-related cues to motivate excessive behavior has been implicated in drug addiction, obesity, and binge eating [1, 2]. For example, in human addicts [3, 4] and animal models of drug self-administration [5, 6], drug cues are important for both maintaining and reinstating drug-seeking behavior. There is, however, considerable individual variation in the influence of reward-associated cues on behavior [1, 7-10]. We have argued that this is due, in part, to individual variation in the degree to which reward-related cues acquire incentive motivational properties (are attributed with incentive salience), and thus acquire the ability to act as incentive stimuli. For example, if a localizable stimulus (the conditional stimulus [CS]) is repeatedly paired with delivery of a food reward (the unconditional stimulus, [US]) the food cue itself becomes attractive, eliciting approach and engagement with it in some rats - these are called sign-trackers (STs) [7]. However, in other rats the food cue itself is not attractive, but instead upon CS presentation these animals approach the location where food will be delivered - these animals are called goal-trackers (GTs) [7]. Yet other rats vacillate between the cue and the goal. Furthermore, a localizable food cue is a more effective conditional reinforcer [1, 7], and is more effective in reinstating food-seeking behavior, in STs than in GTs [11]. Thus, only in some animals does a predictive cue also acquire the properties of an incentive stimulus - the ability to attract, the ability to act as a conditional reinforcer, and to spur (motivate) seeking for its associated reward. Importantly, recent studies suggest that the propensity of animals to attribute incentive salience to a food cue predicts the extent to which a drug cue acquires incentive properties [8, 12]. We aim to determine the extent to which attribution of incentive salience to a food cue predicts the ability of classically conditioned drug cues to control and motivate behavior. This proposal will address the following questions: 1) Does individual variation in the tendency to attribute incentive value to a food cue predict the tendency to attribute incentive value to a drug cue? and 2) What brain regions are engaged by a cocaine cue that has predictive value vs. one that also has incentive value? These studies have the potential to significantly shift how we think about individual vulnerability to addiction and relapse, and to point the way for better targeted interventions. PUBLIC HEALTH RELEVANCE: The environment is saturated with reward-associated cues which can motivate and guide behaviors. While cues are important for guiding normal behavior, such as seeking out food, they can also contribute to compulsive behaviors involved in obesity and addiction which are a major source of health care costs. Understanding why some individuals' behavior is aberrantly guided by cues will have relevance to a variety of human health problems.